Patent GB-776693-A (GB)
Title: New basic ethers of carbinols substituted by endocyclic groups and processes for thepreparation thereof
IPC: C07D295/088
Filed: 1955-04-14
Abstract: The invention comprises compounds of the general formula <FORM:0776693/IV(b)/1> wherein E is a 2:5-endomethylene-cyclohexyl-or a 2:5 - endo - methylene-D 3-cyclohexenyl-group, X is a straight or branched chain alkylene group, Am is a dialkylamino, a 1-pyrrolidyl, a piperidino or a morpholino group, and R1 is the same as E or is a pyridyl or cyclohexyl group or a phenyl group which may be substituted by a halogen atom or an alkyl or alkoxy group, their acid addition and quaternary salts with a compound R2Y wherein R2 is hydrogen, an alkyl group or an aralkyl group and Y is the anion of an inorganic acid, of an alkyl sulphate or of an organic carboxylic acid; and their preparation by either of the following two methods: (1) reaction of the appropriate secondary carbinol <FORM:0776693/IV(b)/2> with a halide Hal-X-Am in the presence of a hydrogen halide binding agent, (2) reaction of an ether <FORM:0776693/IV(b)/3> with an amine H-Am, with in either case, if desired, subsequent conversion to the acid addition or quaternary salt by reaction with an inorganic acid, an organic carboxylic acid, an alkyl or aralkyl halide or a dialkyl sulphate, in the presence or absence of a solvent such as ether, ethanol, acetone, ethyl acetate or benzene.  Suitable binding agents for method (1), which may be carried out at temperatures between 20 DEG  and 150 DEG  C. with or without a solvent such as benzene, toluene or an alkanol, are alkali metals or their amides, alcoholates, hydroxides or carbonates, particularly sodium or potassium or compounds thereof. Method (2) is preferably effected in the presence of a solvent such as benzene, toluene or xylene at temperatures between 50 DEG  and 150 DEG  C. Compounds of the invention containing a 2,5-endomethylene-D 3-cyclohexenyl group may be catalytically hydrogenated to the corresponding 2,5-endomethylene-cyclohexyl compounds.  Salt forming acids referred to are hydrohalic, citric, tartaric, oxalic, sulphuric, phosphoric, acetic, propionic, butyric, caproic, pivalic, maleic, malonic, fumaric, succinic, lactic, malic, pyruvic, benzoic, toluic, cinnamic, mandelic, phthalic, cyclohexane carboxylic, cyclopentyl acetic, cyclohexyl propionic, phenylacetic, hydrocinnamic, 2-furoic, nicotinic and isonicotinic acids. Examples describe the preparation by method (1) of the following compounds: 2,5-endomethylene - D 2 - cyclohexenylphenylcar - binol - b  - dimethylaminoethyl ether and its hydrochloride, the corresponding diethylaminoethyl, dimethylaminopropyl, diethylaminopropyl, 1-pyrrolidylethyl, piperidinoethyl and morpholinoethyl compounds and salts thereof, the b -diethylaminoethyl ethers of bis-(2,5-endomethylene-D 3-cyclohexenyl) carbinol, (2,5-endomethylene-D 3-cyclohexenyl)-(m-tolyl)-, -p-chlorophenyl)- and -(2 - pyridyl) - carbinols, the b -dimethylaminoethyl ethers of (2,5-endomethylene - D 3 - cyclohexenyl) - p - methoxy - phenyl-, -p - bromphenyl, -m - tolyl and -m-butoxy phenyl - carbinols and (2,5 - endo - methylene - cyclohexyl) - phenylcarbinol, and various salts and quaternary derivatives of the above compounds.  The reduction of (2,5-endomethylene - D 3 - cyclohexenyl) phenylcarbinol b -diethylaminoethyl ether and bis-(2,5-endo - methylene - D 3 - cyclohexenyl) - carbinol g -diethylaminopropyl ether to the corresponding cyclohexyl compounds is also described. Further examples describe the preparation by method (2) of (2,5-endomethylene - D 3-cyclohexenyl)-phenylcarbinol g -diethylaminopropyl ether and similar compounds with other tertiary amino groups.  Starting materials.  Carbinols <FORM:0776693/IV(b)/4> are prepared by reacting aldehydes E.CHO with Grignard compounds R1MgHal, or by reacting R1CHO with EMgHal, with subsequent hydrolysis.  They may also be prepared by reduction of the corresponding ketones, preferably, in the case of ketones substituted by unsaturated endocyclic groups, with lithium aluminium hydride.  Halogenated ethers <FORM:0776693/IV(b)/5> are prepared by reacting the above carbinols with compounds Hal-X-Hal, the halogen which is higher in the series F, Cl, Br and I being eliminated as HHal when the two halogen atoms in Hal-X-Hal are different.ALSO:Compounds of the general formula <FORM:0776693/VI/1> wherein E is a 2:5 - endomethylene - cyclohexyl or a 2:5 - endomethylene - c 3 - cyclohexyl group, X is a straight or branched chain alylene group, Am is a diakylamino, a 1 - pyrrolidyl, a piperdino or a morpholino group and R is the same as E or is a pyridyl or cyclohexyl group or a phenyl group which may be substituted by a halogen atom or an akyl or alkoxy group, and their acid addition and quaternary salts with a compound R2Y, wherein R2 is hydrogen, an alkyl group or an arakyl group and Y is the anion of an inorganic acid, of an alkyl sulphate or of an carboxylic acid, are mixed with pharmaceutical carriers such as corn starch, dextrose, lactose and sugar to prepare powders, tablets, pills, dragees and capsules.  To prepare tablets, binders such as pectins, gelatin, gum arabic, methyl cellulose, yeast extract, agar, tragacanth and lubricants such as magnesium stearate, calcium stearate, stearic acid and talc are used.  Injectable solutions in water or isotonic salt solutions may also be prepared.  The compounds have spasmolytic properties.